Retinoid Acid Specifies Neuronal Identity through Graded Expression of Ascl1

John Jacob,Jennifer Kong,Steven Moore,Christopher Milton,Noriaki Sasai,Rosa Gonzalez-Quevedo,Javier Terriente,Itaru Imayoshi,Ryoichiro Kageyama,David G Wilkinson,Bennett G Novitch,James Briscoe

doi:10.1016/j.cub.2013.01.046

John Jacob, Jennifer Kong + Show 10 more

Open Access

https://doi.org/10.1016/j.cub.2013.01.046

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Abstract

SummaryCell diversity and organization in the neural tube depend on the integration of extrinsic signals acting along orthogonal axes. These are believed to specify distinct cellular identities by triggering all-or-none changes in expression of combinations of transcription factors [1]. Under the influence of a common dorsoventral signal, sonic hedgehog, and distinct anterior-posterior (A-P) inductive signals [2, 3], two topographically related progenitor pools that share a common transcriptional code produce serotonergic and V3 neurons in the hindbrain and spinal cord, respectively [4–7]. These neurons have different physiological properties, functions, and connectivity [8, 9]. Serotonergic involvement in neuropsychiatric diseases has prompted greater characterization of their postmitotic repertoire of fate determinants, which include Gata2, Lmx1b, and Pet1 [10], whereas V3 neurons express Sim1 [4]. How distinct serotonergic and V3 neuronal identities emerge from progenitors that share a common transcriptional code is not understood. Here, we show that changes in retinoid activity in these two progenitor pools determine their fates. Retinoids, via Notch signaling, control the expression level in progenitors of the transcription factor Ascl1, which selects serotonergic and V3 neuronal identities in a dose-dependent manner. Therefore, quantitative differences in the expression of a single component of a transcriptional code can select distinct cell fates.

Highlights

RAR403 markedly upregulated Ascl1 expression in the p3[V3] domain by E5 24 hr after the downregulation of the Notch pathway
All three factors have been shown to be necessary for the generation of 5HT neurons, and Nkx2.2 and Ascl1 are critical for V3 neurogenesis [4, 5, 11, 12]
Consistent with its expression in spinal cord p3 progenitors, Foxa2 is required for the generation of V3 neurons (Figures S1B, S1D, and S1E) [13]

Summary

Introduction

RAR403 markedly upregulated Ascl1 expression in the p3[V3] domain by E5 24 hr after the downregulation of the Notch pathway Misexpression of Hes1, an effector of Notch signaling, in the caudal hindbrain of the chick lowered the expression of Ascl1 in p3[5HT] progenitors to levels comparable to the expression of Ascl1 in spinal cord p3 progenitors (control p3[5HT] = 221.9 [mean] 6 20.9 [SD]; Hes1 electroporation p3[5HT] = 123.4 6 8.7; control p3[V3] = 119.8 6 22.1) (Figure 2I).

Results

Conclusion